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[Federal Register Volume 80, Number 146 (Thursday, July 30, 2015)]
[Rules and Regulations]
[Pages 45438-45443]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-18738]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[EPA-HQ-OPP-2013-0138; FRL-9923-86]

Isofetamid; Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for residues of 
isofetamid in or on multiple commodities that are identified and 
discussed later in this document. ISK Biosciences Corporation requested 
these tolerances under the Federal Food, Drug, and Cosmetic Act 
(FFDCA).

DATES: This regulation is effective July 30, 2015. Objections and 
requests for hearings must be received on or before September 28, 2015, 
and must be filed in accordance with the instructions provided in 40 
CFR part 178 (see also Unit I.C. of the SUPPLEMENTARY INFORMATION).

ADDRESSES: The docket for this action, identified by docket 
identification (ID) number EPA-HQ-OPP-2013-0138, is available at http://www.regulations.gov or at the Office of Pesticide Programs Regulatory 
Public Docket (OPP Docket) in the Environmental Protection Agency 
Docket Center (EPA/DC), West William Jefferson Clinton Bldg., Rm. 3334, 
1301 Constitution Ave. NW., Washington, DC 20460-0001. The Public 
Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through 
Friday, excluding legal holidays. The telephone number for the Public 
Reading Room is (202) 566-1744, and the telephone number for the OPP 
Docket is (703) 305-5805. Please review the visitor instructions and 
additional information about the docket available at http://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Susan Lewis, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave. NW., Washington, DC 20460-0001; telephone 
number: 703-305-7090; email address: RDFRNotices@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    You may be potentially affected by this action if you are an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
The following list of North American Industrial Classification System 
(NAICS) codes is not intended to be exhaustive, but rather provides a 
guide to help readers determine whether this document applies to them. 
Potentially affected entities may include:
     Crop production (NAICS code 111).
     Animal production (NAICS code 112).
     Food manufacturing (NAICS code 311).
     Pesticide manufacturing (NAICS code 32532).

B. How can I get electronic access to other related information?

    You may access a frequently updated electronic version of EPA's 
tolerance

[[Page 45439]]

regulations at 40 CFR part 180 through the Government Printing Office's 
e-CFR site at http://www.ecfr.gov/cgi-bin/text-idx?&c=ecfr&tpl=/ecfrbrowse/Title40/40tab_02.tpl.

C. How can I file an objection or hearing request?

    Under FFDCA section 408(g), 21 U.S.C. 346a, any person may file an 
objection to any aspect of this regulation and may also request a 
hearing on those objections. You must file your objection or request a 
hearing on this regulation in accordance with the instructions provided 
in 40 CFR part 178. To ensure proper receipt by EPA, you must identify 
docket ID number EPA-HQ-OPP-2013-0138 in the subject line on the first 
page of your submission. All objections and requests for a hearing must 
be in writing, and must be received by the Hearing Clerk on or before 
September 28, 2015. Addresses for mail and hand delivery of objections 
and hearing requests are provided in 40 CFR 178.25(b).
    In addition to filing an objection or hearing request with the 
Hearing Clerk as described in 40 CFR part 178, please submit a copy of 
the filing (excluding any Confidential Business Information (CBI)) for 
inclusion in the public docket. Information not marked confidential 
pursuant to 40 CFR part 2 may be disclosed publicly by EPA without 
prior notice. Submit the non-CBI copy of your objection or hearing 
request, identified by docket ID number EPA-HQ-OPP-2013-0138, by one of 
the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the online instructions for submitting comments. Do not submit 
electronically any information you consider to be CBI or other 
information whose disclosure is restricted by statute.
     Mail: OPP Docket, Environmental Protection Agency Docket 
Center (EPA/DC), (28221T), 1200 Pennsylvania Ave. NW., Washington, DC 
20460-0001.
     Hand Delivery: To make special arrangements for hand 
delivery or delivery of boxed information, please follow the 
instructions at http://www.epa.gov/dockets/contacts.html. Additional 
instructions on commenting or visiting the docket, along with more 
information about dockets generally, is available at http://www.epa.gov/dockets.

II. Summary of Petitioned-For Tolerance

    In the Federal Register of June 5, 2013 (78 FR 33785) (FRL-9386-2), 
EPA issued a document pursuant to FFDCA section 408(d)(3), 21 U.S.C. 
346a(d)(3), announcing the filing of a pesticide petition (PP 3F8142) 
by ISK Biosciences Corporation, 7470 Auburn Road, Suite A, Concord, 
Ohio 44077. The petition requested that 40 CFR part 180 be amended by 
establishing tolerances for residues of the fungicide isofetamid, N-
[1,1-dimethyl-2-[2-methyl-4-(1-methylethoxy)phenyl]-2-oxoethyl]-3-
methyl-2-thiophenecarboxamide in or on almond at 0.02 parts per million 
(ppm); almond, hulls at 0.2 ppm; lettuce, head at 6.0 ppm; lettuce, 
leaf at 7.0 ppm; low growing berry crop subgroup 13-07G at 4.0 ppm; 
rapeseed, crop subgroup 20A at 0.04 ppm; and small fruit vine climbing 
crop subgroup 13-07F at 3.0 ppm. That document referenced a summary of 
the petition prepared by ISK Biosciences Corporation, the registrant, 
which is available in the docket, http://www.regulations.gov. There 
were no comments received in response to the notice of filing.
    Based upon review of the data supporting the petition, EPA has 
determined that additional tolerances are necessary; revised some of 
the proposed tolerances; and corrected some commodity definitions for 
the tolerances. The reasons for these changes are explained in Unit 
IV.C.

III. Aggregate Risk Assessment and Determination of Safety

    Section 408(b)(2)(A)(i) of FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) of FFDCA defines ``safe'' to mean that ``there is a 
reasonable certainty that no harm will result from aggregate exposure 
to the pesticide chemical residue, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information.'' This includes exposure through drinking water and in 
residential settings, but does not include occupational exposure. 
Section 408(b)(2)(C) of FFDCA requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance and to ``ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue. . . 
.''
    Consistent with FFDCA section 408(b)(2)(D), and the factors 
specified in FFDCA section 408(b)(2)(D), EPA has reviewed the available 
scientific data and other relevant information in support of this 
action. EPA has sufficient data to assess the hazards of and to make a 
determination on aggregate exposure for isofetamid including exposure 
resulting from the tolerances established by this action. EPA's 
assessment of exposures and risks associated with isofetamid follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
children. The toxicology database is complete for isofetamid. In 
repeated dose studies, the liver was the primary target organ in the 
rat, mouse, and dog, as indicated by increased liver weights, changes 
in the clinical chemistry values, and liver hypertrophy. A second 
target organ was the thyroid in the rat and dog, as indicated by 
changes in thyroid weights and histopathology. Adrenal weight changes 
were observed in the subchronic rat and dog studies. In the rat and 
dog, the dose levels where toxicity was observed were similar or higher 
in the chronic studies compared with the respective subchronic studies, 
showing an absence of progression of liver toxicity with time. There 
was no evidence of carcinogenicity in the rat or mouse cancer studies; 
the mutagenicity battery was negative. There are no genotoxicity, 
neurotoxicity, or immunotoxicity concerns observed in the available 
toxicity studies. Developmental toxicity was not observed in the rat or 
rabbit, and offspring effects such as decreased body weight were seen 
only in the presence of parental toxicity in the multi-generation rat 
study. Isofetamid is classified as ``Not Likely to be Carcinogenic to 
Humans'' based on the absence of increased tumor incidence in 
acceptable/guideline carcinogenicity studies in rats and mice. 
Isofetamid is not acutely toxic; it is classified as Toxicity Category 
III for acute oral and dermal exposure, and Toxicity Category IV for 
inhalation exposure. Furthermore, it is not irritating to the eye or 
skin, and it is not a dermal sensitizer. Specific information on the 
studies received and the nature of the adverse effects caused by 
isofetamid as well as the no-observed-adverse-effect-level (NOAEL) and 
the lowest-observed-adverse-effect-level (LOAEL) from the toxicity 
studies can be found at http://www.regulations.gov in document 
Isofetamid. Aggregate Human Health Risk Assessment for the Proposed New 
Uses of the New Active Fungicide,

[[Page 45440]]

including Agricultural Uses on Almonds, Lettuce, Small Vine Climbing 
Fruits (Crop Subgroup 13-07F), Low Growing Berries (Crop Subgroup 13-
07G), and Rapeseed (Crop Subgroup 20A); and Uses on Turfgrass 
(including Golf Courses, Sod Farms, Seed Farms, Recreational Fields, 
and Commercial/Residential Lawns) at pages 12-18 in docket ID number 
EPA-HQ-OPP-2013-0138.

B. Toxicological Points of Departure/Levels of Concern

    Once a pesticide's toxicological profile is determined, EPA 
identifies toxicological points of departure (POD) and levels of 
concern to use in evaluating the risk posed by human exposure to the 
pesticide. For hazards that have a threshold below which there is no 
appreciable risk, the toxicological POD is used as the basis for 
derivation of reference values for risk assessment. PODs are developed 
based on a careful analysis of the doses in each toxicological study to 
determine the dose at which no adverse effects are observed (the NOAEL) 
and the lowest dose at which adverse effects of concern are identified 
(the LOAEL). Uncertainty/safety factors are used in conjunction with 
the POD to calculate a safe exposure level--generally referred to as a 
population-adjusted dose (PAD) or a reference dose (RfD)--and a safe 
margin of exposure (MOE). For non-threshold risks, the Agency assumes 
that any amount of exposure will lead to some degree of risk. Thus, the 
Agency estimates risk in terms of the probability of an occurrence of 
the adverse effect expected in a lifetime. For more information on the 
general principles EPA uses in risk characterization and a complete 
description of the risk assessment process, see http://www.epa.gov/pesticides/factsheets/riskassess.htm.
    A summary of the toxicological endpoints for isofetamid used for 
human risk assessment is shown in Table 1 of this unit.

  Table 1--Summary of Toxicological Doses and Endpoints for Isofetamid for Use in Human Health Risk Assessment
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                                    Point of departure
        Exposure/scenario            and uncertainty/     RfD, PAD, LOC for     Study and toxicological effects
                                      safety factors       risk assessment
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Acute Dietary (All Populations)    A toxicity endpoint was not identified.
                                   Toxicological effects attributable to a single exposure (dose) were not
                                    observed in oral toxicity studies.
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Chronic dietary (All populations)  NOAEL = 76.6 mg/kg/   Chronic RfD = 0.77   Reproduction and fertility effects
                                    day                   mg/kg/day            (rat)
                                   UFA = 10X...........  cPAD = 0.77 mg/kg/   LOAEL = 679/775 mg/kg/day based on
                                   UFH = 10X...........   day.                 hepatocellular hypertrophy in the
                                   FQPA SF = 1X........                        liver and follicular cell
                                                                               hypertrophy in the thyroid in
                                                                               both sexes and generations,
                                                                               decreased spleen weights and
                                                                               cytoplasmic eosinophilic
                                                                               inclusion bodies in the liver of
                                                                               F1 males, and decreased pup body
                                                                               weight in both sexes and
                                                                               generations.
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Incidental oral short-term (1 to   NOAEL = 76.6 mg/kg/   Residential LOC for  Reproduction and fertility effects
 30 days) and Incidental oral       day                   MOE = 100.           (rat)
 intermediate-term (1 to 6         UFA = 10X...........                       LOAEL = 679/775 mg/kg/day based on
 months)                           UFH = 10X...........                        hepatocellular hypertrophy in the
                                   FQPA SF = 1X........                        liver and follicular cell
                                                                               hypertrophy in the thyroid in
                                                                               both sexes and generations,
                                                                               decreased spleen weights and
                                                                               cytoplasmic eosinophilic
                                                                               inclusion bodies in the liver of
                                                                               F1 males, and decreased pup body
                                                                               weight in both sexes and
                                                                               generations
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Dermal Short-Term (1-30 days)      A toxicity endpoint was not identified.
                                   Systemic toxicity was not seen in 28-day dermal toxicity in rats up to the
                                    limit dose (1,000 mg/kg/day). There are no concerns for developmental or
                                    reproductive toxicity or neurotoxicity in rat and rabbit studies.
----------------------------------------------------------------------------------------------------------------
Inhalation short-term (1 to 30     NOAEL = 76.6 mg/kg/   Residential LOC for  Reproduction and fertility effects
 days)                              day                   MOE = 100            (rat)
                                   UFA = 10X...........                       LOAEL = 679/775 mg/kg/day based on
                                   UFH = 10X...........                        hepatocellular hypertrophy in the
                                   FQPA SF = 1X........                        liver and follicular cell
                                                                               hypertrophy in the thyroid in
                                                                               both sexes and generations,
                                                                               decreased spleen weights and
                                                                               cytoplasmic eosinophilic
                                                                               inclusion bodies in the liver of
                                                                               F1 males, and decreased pup body
                                                                               weight in both sexes and
                                                                               generations.
----------------------------------------------------------------------------------------------------------------
Cancer (Oral, dermal, inhalation)  Classification: ``Not likely to be Carcinogenic to Humans'' based on the
                                    absence of significant tumor increases in two adequate rodent
                                    carcinogenicity studies.
----------------------------------------------------------------------------------------------------------------
FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. LOC = level
  of concern. mg/kg/day = milligram/kilogram/day. MOE = margin of exposure. NOAEL = no-observed-adverse-effect-
  level. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. UF = uncertainty factor.
  UFA = extrapolation from animal to human (interspecies). UFDB = to account for the absence of data or other
  data deficiency. UFH = potential variation in sensitivity among members of the human population
  (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term
  risk assessment.

C. Exposure Assessment

    1. Dietary exposure from food and feed uses. EPA assessed dietary 
exposures from isofetamid in food as follows:
    i. Acute exposure. Quantitative acute dietary exposure and risk 
assessments are performed for a food-use pesticide, if a toxicological 
study has indicated the possibility of an effect of concern occurring 
as a result of a 1-day or single exposure. No such effects were 
identified in the toxicological studies for isofetamid; therefore, a 
quantitative acute dietary exposure assessment is unnecessary.

[[Page 45441]]

    ii. Chronic exposure. In conducting the chronic dietary exposure 
assessment, EPA used the 2003-2008 food consumption data from the 
USDA's National Health and Nutrition Examination Survey, What We Eat in 
America (NHANES/WWEIA). A partially refined chronic (food and drinking 
water) dietary assessment was conducted assuming mean field trial 
residues of the combined residues of parent and GPTC for all proposed 
crops and 100% CT. Empirical and default processing factors were used 
as available.
    iii. Cancer. Based on the data summarized in Unit III.A., EPA has 
concluded that isofetamid does not pose a cancer risk to humans. 
Therefore, a dietary exposure assessment for the purpose of assessing 
cancer risk is unnecessary.
    iv. Anticipated residue and percent crop treated (PCT) information. 
EPA did not use PCT information in the dietary assessment for 
isofetamid. Mean field trial residues of the combined residues of 
parent and GPTC were used.
    2. Dietary exposure from drinking water. The Agency used screening 
level water exposure models in the dietary exposure analysis and risk 
assessment for isofetamid in drinking water. These simulation models 
take into account data on the physical, chemical, and fate/transport 
characteristics of isofetamid. Further information regarding EPA 
drinking water models used in pesticide exposure assessment can be 
found at http://www.epa.gov/oppefed1/models/water/index.htm.
    Based on the Pesticide Flooded Application Model and the Pesticide 
Root Zone Model Ground Water (PRZM GW) the estimated drinking water 
concentrations (EDWCs) of isofetamid for chronic exposures for non-
cancer assessments are estimated to be 110 ppb for surface water and 43 
ppb for ground water.
    Modeled estimates of drinking water concentrations were directly 
entered into the dietary exposure model. For chronic dietary risk 
assessment, the water concentration value of 110 ppb was used to assess 
the contribution from drinking water.
    3. From non-dietary exposure. The term ``residential exposure'' is 
used in this document to refer to non-occupational, non-dietary 
exposure (e.g., for lawn and garden pest control, indoor pest control, 
termiticides, and flea and tick control on pets).
    Isofetamid is currently under review for registering the following 
uses that could result in residential exposures: Foliar and systemic 
fungicide for control in turfgrass including golf courses, residential 
lawns, and recreational turfgrass. Since there may be residential use 
sites, residential handler exposure and risk estimates were calculated 
for all possible residential exposure scenarios. Including all possible 
residential exposure scenarios provides a conservative and health 
protective assessment for the potential for homeowners to use the 
professionally labeled products on residential use sites. Since there 
is no dermal toxicity endpoint, the residential handler assessment only 
includes the inhalation route of exposure. Residential handler exposure 
is expected to be short-term in duration as a maximum of eight 
applications are allowed per year. Thus, intermediate-term exposures 
are not likely because of the intermittent nature of applications by 
homeowners. Unit exposure values and estimates for area treated or 
amount handled were taken from the Agency's 2012 Residential SOPs \1\ 
(Lawns/Turf). The algorithms used to estimate exposure and dose for 
residential handlers can be found in the 2012 Residential SOPs \2\ 
(Lawns/Turf). Risk estimates of all possible scenarios are not of 
concern. Short-term inhalation MOEs range from 850,000 to 18,000,000. 
Further information regarding EPA standard assumptions and generic 
inputs for residential exposures may be found at http://www.epa.gov/pesticides/trac/science/trac6a05.pdf.
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    \1\ Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html.
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    4. Cumulative effects from substances with a common mechanism of 
toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when 
considering whether to establish, modify, or revoke a tolerance, the 
Agency consider ``available information'' concerning the cumulative 
effects of a particular pesticide's residues and ``other substances 
that have a common mechanism of toxicity.''
    EPA has not found isofetamid to share a common mechanism of 
toxicity with any other substances, and isofetamid does not appear to 
produce a toxic metabolite produced by other substances. For the 
purposes of this tolerance action, therefore, EPA has assumed that 
isofetamid does not have a common mechanism of toxicity with other 
substances. For information regarding EPA's efforts to determine which 
chemicals have a common mechanism of toxicity and to evaluate the 
cumulative effects of such chemicals, see EPA's Web site at http://www.epa.gov/pesticides/cumulative.

D. Safety Factor for Infants and Children

    1. In general. Section 408(b)(2)(C) of FFDCA provides that EPA 
shall apply an additional tenfold (10X) margin of safety for infants 
and children in the case of threshold effects to account for prenatal 
and postnatal toxicity and the completeness of the database on toxicity 
and exposure unless EPA determines based on reliable data that a 
different margin of safety will be safe for infants and children. This 
additional margin of safety is commonly referred to as the FQPA Safety 
Factor (SF). In applying this provision, EPA either retains the default 
value of 10X, or uses a different additional safety factor when 
reliable data available to EPA support the choice of a different 
factor.
    2. Prenatal and postnatal sensitivity. There is no evidence of 
developmental toxicity or reproductive susceptibility, and there are no 
residual uncertainties concerning pre- or post-natal toxicity or 
exposure.
    3. Conclusion. EPA has determined that reliable data show the 
safety of infants and children would be adequately protected if the 
FQPA SF were reduced to 1X. That decision is based on the following 
findings:
    i. The toxicity database for isofetamid is complete.
    ii. There is no indication that isofetamid is a neurotoxic chemical 
and there is no need for a developmental neurotoxicity study or 
additional UFs to account for neurotoxicity.
    iii. There is no evidence that isofetamid results in increased 
susceptibility in in utero rats or rabbits in the prenatal 
developmental studies or in young rats in the 2-generation reproduction 
study.
    iv. There are no residual uncertainties identified in the exposure 
databases. The dietary food exposure assessments were performed based 
on 100 PCT and average (mean) field trial residues. EPA made 
conservative (protective) assumptions in the ground and surface water 
modeling used to assess exposure to isofetamid in drinking water. EPA 
used similarly conservative assumptions to assess post application 
exposure of children as well as incidental oral exposure of toddlers. 
These assessments will not underestimate the exposure and risks posed 
by isofetamid.

E. Aggregate Risks and Determination of Safety

    EPA determines whether acute and chronic dietary pesticide 
exposures are safe by comparing aggregate exposure estimates to the 
acute PAD (aPAD) and chronic PAD (cPAD). For linear cancer

[[Page 45442]]

risks, EPA calculates the lifetime probability of acquiring cancer 
given the estimated aggregate exposure. Short-, intermediate-, and 
chronic-term risks are evaluated by comparing the estimated aggregate 
food, water, and residential exposure to the appropriate PODs to ensure 
that an adequate MOE exists.
    1. Acute risk. An acute aggregate risk assessment takes into 
account acute exposure estimates from dietary consumption of food and 
drinking water. No adverse effect resulting from a single oral exposure 
was identified and no acute dietary endpoint was selected. Therefore, 
isofetamid is not expected to pose an acute risk.
    2. Chronic risk. Using the exposure assumptions described in this 
unit for chronic exposure, EPA has concluded that chronic exposure to 
isofetamid from food and water will utilize MS) method (Document Number JSM0119; MRID 
49011967) is available to enforce the tolerance expression.

B. International Residue Limits

    In making its tolerance decisions, EPA seeks to harmonize U.S. 
tolerances with international standards whenever possible, consistent 
with U.S. food safety standards and agricultural practices. EPA 
considers the international maximum residue limits (MRLs) established 
by the Codex Alimentarius Commission (Codex), as required by FFDCA 
section 408(b)(4). The Codex Alimentarius is a joint United Nations 
Food and Agriculture Organization/World Health Organization food 
standards program, and it is recognized as an international food safety 
standards-setting organization in trade agreements to which the United 
States is a party. EPA may establish a tolerance that is different from 
a Codex MRL; however, FFDCA section 408(b)(4) requires that EPA explain 
the reasons for departing from the Codex level.
    The Codex has not established any MRLs for isofetamid. Canada is 
concurrently establishing tolerances for all of the same commodities 
identified in this document except almond hulls because Canada does not 
set tolerances on livestock feed commodities. Canada's recommended 
tolerance levels for these commodities are the same as the U.S. 
established tolerance levels. The tolerance expression for the U.S. and 
Canada is the same, with isofetamid as the residue of concern for 
primary crops.

C. Revisions to Petitioned-For Tolerances

    The Agency has made revisions to some of the petitioned-for 
tolerance levels based on the following reasons:
    1. Organization for Economic Cooperation and Development (OECD) 
tolerance calculation procedures;
    2. The parent only is the residue of concern for primary crop 
tolerances rather than parent and the metabolite GPTC; and
    3. The concentration of residues in two processed commodities.
    Since all residues of isofetamid (parent) were nondetectable (pre>
```